Disruption of the dystrophin-sarcoglycan complex (DGC) has been identified as the molecular basis for impaired sarcolemmal membrane integrity and increased cytosolic Ca2+ concentration [Ca2+]i in some muscular dystrophies (MDs). This increased [Ca2+]i contributes to myofiber death via activation of calpains (Ca2+-dependent neutral proteases). Moreover, the rate of Ca2+ sparks significantly increases in dystrophic myofibers, consistent with defective leaky SR Ca2+ release channels. Indeed, recent studies have identified RyR1 mutations that are genetically linked to MDs. We recently showed that S-nitrosylation of the type 1 ryanodine receptor (RyR1) in skeletal muscle causes FKBP12 (calstabin1) depletion from the channel complex resulting in SR Ca2+ leak that contributes to muscle weakness and damage in the murine mdx model of Duchenne muscular dystrophy. Treatment with S107, a novel small molecule derived from 1,4-benzothiazepines, that inhibits calstabin-1 depletion from the RyR1 complex, improved exercise capacity, muscle force and reduced muscle damage in dystrophic mice. The applicant proposes to test the hypothesis that leaky RyR1 and RyR2 channels due to hypernitrosylation of the channels are a common feature of MDs that involve disruption of the DCG. Furthermore, by preventing RyR1 and RyR2 leak using a novel compound, S107, the applicant will seek to reduce muscle damage, cardiac abnormalities, and improve exercise capacity in murine models of MD. The proposed studies are significant because they may identify a novel mechanism underlying intracellular Ca2+ leak that contributes to pathology in MD and could be a therapeutic target in patients.